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dc.contributor.authorEvnouchidou, Irini
dc.contributor.authorMomburg, Frank
dc.contributor.authorPapakyriakou, Athanasios
dc.contributor.authorChroni, Angeliki
dc.contributor.authorLeondiadis, Leondios
dc.contributor.authorChang, Shih-Chung
dc.contributor.authorGoldberg, Alfred L.
dc.contributor.authorStratikos, Efstratios
dc.date.accessioned2011-06-30T17:40:48Z
dc.date.issued2008
dc.identifier.citationEvnouchidou, Irini, Frank Momburg, Athanasios Papakyriakou, Angeliki Chroni, Leondios Leondiadis, Shih-Chung Chang, Alfred L. Goldberg, and Efstratios Stratikos. 2008. The internal sequence of the peptide-substrate determines Its N-terminus trimming by ERAP1. PLoS ONE 3(11): e3658.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:4930584
dc.description.abstractBackground: Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims N-terminally extended antigenic peptide precursors down to mature antigenic peptides for presentation by major histocompatibility complex (MHC) class I molecules. ERAP1 has unique properties for an aminopeptidase being able to trim peptides in vitro based on their length and the nature of their C-termini. Methodology/Principal Findings: In an effort to better understand the molecular mechanism that ERAP1 uses to trim peptides, we systematically analyzed the enzyme's substrate preferences using collections of peptide substrates. We discovered strong internal sequence preferences of peptide N-terminus trimming by ERAP1. Preferences were only found for positively charged or hydrophobic residues resulting to trimming rate changes by up to 100 fold for single residue substitutions and more than 40,000 fold for multiple residue substitutions for peptides with identical N-termini. Molecular modelling of ERAP1 revealed a large internal cavity that carries a strong negative electrostatic potential and is large enough to accommodate peptides adjacent to the enzyme's active site. This model can readily account for the strong preference for positively charged side chains. Conclusions/Significance: To our knowledge no other aminopeptidase has been described to have such strong preferences for internal residues so distal to the N-terminus. Overall, our findings indicate that the internal sequence of the peptide can affect its trimming by ERAP1 as much as the peptide's length and C-terminus. We therefore propose that ERAP1 recognizes the full length of its peptide-substrate and not just the N- and C- termini. It is possible that ERAP1 trimming preferences influence the rate of generation and the composition of antigenic peptides in vivo.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0003658en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2573961/pdf/en_US
dash.licenseLAA
dc.subjectbiochemistryen_US
dc.subjectbiocatalysisen_US
dc.subjectprotein chemistryen_US
dc.subjectprotein chemistry and proteomicsen_US
dc.subjectbiophysicsen_US
dc.subjectimmunologyen_US
dc.subjectantigen processing and recognitionen_US
dc.titleThe Internal Sequence of the Peptide-Substrate Determines Its N-Terminus Trimming by ERAP1en_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorGoldberg, Alfred L.
dc.date.available2011-06-30T17:40:48Z
dash.affiliation.otherHMS^Cell Biologyen_US
dc.identifier.doi10.1371/journal.pone.0003658*
dash.contributor.affiliatedGoldberg, Alfred


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